The invention relates to oxadiazole derivatives useful as intermediates for producing pharmaceuticals, a process for producing the same, and a process for producing 1,3,4-oxadiazole derivatives by using the intermediate.
More specifically, the invention relates to
(1) a compound represented by formula (I): 
xe2x80x83(wherein all symbols have the same meanings as described below), a non-toxic salt thereof, and a hydrate thereof;
(2) a process for producing the same, and
(3) a process for producing a compound represented by formula (II): 
xe2x80x83(wherein all symbols have the same meanings as described below), comprising using the same.
WO9824806 discloses that a compound represented by formula (W-a): 
a compound represented by formula (W-b): 
and a compound represented by formula (W-c): 
(wherein Xw and Yw independently represent an oxygen atom, a sulfur atom or a nitrogen atom which may be substituted; R1w represents various substituents, such as an alkyl group which may be substituted, a hydroxyl group, and an amino group; R2w and R3w independently represent a hydrogen atom or various substituents, such as an alkyl group which may be substituted; Aw represents a single bond, a xe2x80x94COxe2x80x94 group, an xe2x80x94NHCOxe2x80x94 group, an xe2x80x94SO2xe2x80x94 group, or the like; R4w represents a hydrogen atom or various substituents, such as an alkyl group which may be substituted; Bw represents an xe2x80x94SO2xe2x80x94 group, a xe2x80x94COxe2x80x94 group, or the like; and R11w, R12w, and Ew are taken together to form a ring, with the proviso that these definitions are abstracts from the disclosure are useful as a serine protease (especially an elastase) inhibitor.
Upon reviewing the specification in detail, it discloses a compound represented by formula (W-c-1): 
(wherein R1w has the same meaning as described above) among the compounds represented by general formula (W-c).
In the specification, various inhibitors are prepared using, as a key intermediate, a compound represented by formula (W-1): 
(wherein R1w has the same meaning as described above). According to the specification, the compound represented by formula (W-1) is produced in accordance with reaction scheme 1 or 2 shown below.
In reaction scheme 1, xe2x80x9cCbzxe2x80x9d stands for a benzyloxycarbonyl group; xe2x80x9cPyxe2x80x9d, pyridine; xe2x80x9cTEAxe2x80x9d, triethylamine; xe2x80x9cDMSOxe2x80x9d, dimethyl sulfoxide; xe2x80x9cAc2Oxe2x80x9d, acetic anhydride; xe2x80x9cEDCxe2x80x9d, 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride; xe2x80x9cHOBtxe2x80x9d, 1-hydroxybenzotriazole; xe2x80x9cDMFxe2x80x9d, dimethylformamide; xe2x80x9cNMMxe2x80x9d, N-methylmorpholine; xe2x80x9cTsxe2x80x9d, a tosyl group; xe2x80x9cTFAxe2x80x9d, trifluoroacetic acid; xe2x80x9cMexe2x80x9d, a methyl group; and xe2x80x9cEtxe2x80x9d, an ethyl group. 
In reaction scheme 2, xe2x80x9cBocxe2x80x9d stands for a t-butoxycarbonyl group; xe2x80x9ciBuxe2x80x9d, an isobutyl group; xe2x80x9cDIBALxe2x80x9d, diisobutylaluminum hydride; and xe2x80x9cn-BuLixe2x80x9d, n-butyl lithium. Other symbols have the same meanings as described above. 
The specification also discloses that the compound represented by formula (W-c-1) among the compounds represented by formula (W-c) is produced using the compound represented by formula (W-1) in accordance with reaction scheme 3 shown below.
In reaction scheme 3, xe2x80x9cT2wxe2x80x9d represents a hydrogen atom or a benzyloxycarbonylamino group, and other symbols are as defined above. The oxidation using the Dess-Martin reagent and the Swern oxidation are known oxidations. 
The process according to reaction scheme 1 involves a number of steps (10 steps) for producing the compound represented by formula (W-1) so that it is insufficient in efficiency.
The present inventors have conducted extensive studies seeking an efficient process for producing the compounds represented by formula (W-c-1) that are promising as pharmaceuticals. As a result, they have found a process for producing the compound represented by formula (II) shown in reaction scheme 4, in which novel compounds represented by formulae (I-1) and (I-2), namely, the compounds represented by formula (I) are used as a key intermediate.
In reaction scheme 4, R2, R3 and R4 each independently represents:
(1) a C1-8 alkyl group,
(2) a C3-7 cycloalkyl group,
(3) a phenyl group,
(4) a phenyl group substituted with one to three of a C1-8 alkyl group, a C1-8 alkoxy group, a halogen atom, a trifluoromethyl group, and a trifluoromethoxy group, or
(5) a 3,4-methylenedioxyphenyl group; or
(6) R3 and R4 are taken together to represent a C2-6 alkylene group; and
R5 and R6 each independently represents an amino-protective group. 
The inventors have experimented the conventional processes shown in reaction schemes 2 and 3 to find that the overall synthesis yield of a compound represented by formula (II) in which R2, R3 and R4 all represent a methyl group was 18% through six steps (see Comparative Examples described below, in which a compound represented by formula (W-XI) was used as a starting material.). In the Comparative Examples, the Swern oxidation was used as an oxidation to produce a compound represented by formula (W-XVII).
According to the process of the invention shown in reaction scheme 4, on the other hand, the overall synthesis yield of a compound represented by formula (II) wherein R1w is a t-butyl group was 65% through four steps (see Examples described below). In the Examples, a t-butoxycarbonyl group was used as an amino-protective group R5 in the compound represented by formulae (V) and the compound represented by formula (I-2), and a benzyloxycarbonyl group was used as an amino-protective group R6 in the compound represented by formula (IV) and the compound represented by formula (III).
Hence, the process of the invention makes it possible to obtain the compound represented by formula (II) through fewer steps in a higher yield. In other words, the process of the invention provides a desired compound through steps less by two in a three- to four-fold yield.
The present inventors have found that the compound represented by formula (II) can be prepared efficiently by the process represented by reaction scheme 4 which uses the novel compounds represented by formula (I) and thus completed the present invention.
The present invention relates to
1) a compound represented by general formula (I): 
xe2x80x83(wherein
R1 represents a hydrogen atom or an amino-protective group;
R2, R3 and R4 each independently represents
(1) a C1-8 alkyl group,
(2) a C3-7 cycloalkyl group,
(3) a phenyl group,
(4) a phenyl group substituted with one to three of a C1-8 alkyl group, a C1-8 alkoxy group, a halogen atom, a trifluoromethyl group, and a trifluoromethoxy group, or
(5) a 3,4-methylenedioxyphenyl group; or
(6) R3 and R4 are taken together to represent a C2-6 alkylene group), a non-toxic salt thereof, and a hydrate thereof,
2) a process for producing the compound represented by formula (I), and
3) a process for producing a compound represented by formula (II): 
xe2x80x83(wherein all symbols have the same meanings as described above), comprising using the compound represented by formula (I).
The term xe2x80x9cC1-8 alkyl groupxe2x80x9d as used herein means a methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl group or an isomer thereof.
The term xe2x80x9cC3-7 cycloalkyl groupxe2x80x9d as used herein means a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.
The term xe2x80x9cC1-8 alkoxy groupxe2x80x9d as used herein means a methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy or octyloxy group or an isomer thereof.
The term xe2x80x9chalogen atomxe2x80x9d as used herein means fluorine, chlorine, bromine or iodine.
The term xe2x80x9cC2-6 alkylene groupxe2x80x9d as used herein means an ethylene, trimethylene, tetramethylene, pentamethylene or hexamethylene group.
The amino-protective group represented by R1, R5 or R6 in the invention includes a benzyloxycarbonyl group, a t-butoxycarbonyl group, a trifluoroacetyl group and the like, but is not limited thereto, so long as it is a group which is easily and selectively removable. For example, those described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York (1991) are useful, such as methoxycarbonyl, ethoxycarbonyl, 9-fluorenylmethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, 1,1-dimethylpropynyloxycarbonyl, 1-methyl-1-phenylethoxycarbonyl, 1-methyl-1-(4-biphenylyl)ethoxycarbonyl, 1,1-dimethyl-2-haloethoxycarbonyl, 1,1-dimethyl-2-cyanoethoxycarbonyl, t-butoxycarbonyl, cyclobutoxycarbonyl, 1-methylcyclobutoxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, cinnamyloxycarbonyl, 8-quinolyloxycarbonyl, N-hydroxypiperidinyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 3,4-dimethoxy-6-nitrobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 5-benzisoxazolylmethyloxycarbonyl, 9-anthrylmethyloxycarbonyl, diphenylmethyloxycarbonyl, isonicotinyloxycarbonyl, benzylthiocarbonyl, Nxe2x80x2-phenylaminothiocarbonyl, formyl, acetyl, chloroacetyl, trichloroacetyl, trifluoroacetyl, benzoyl, allyl, phenylacetyl, methoxymethyl, benzyloxymethyl, 2,4-dinitrophenyl, 2-nitrobenzyl, 2-(trimethylsilyl)ethoxymethyl, benzyl, triphenylmethyl, p-toluenesulfonyl, benzenesulfonyl and benzylsulfonyl.
The amino-protective group represented by R1 and R5 is preferably a t-butoxycarbonyl group or a benzyloxycarbonyl group, and more preferably a t-butoxycarbonyl group.
The amino-protective group represented by R6 is preferably a benzyloxycarbonyl group.
In the present invention, the group represented by 
is preferably a group in which R2, R3 and R4 each represents a C1-8 alkyl group; a group in which R2 represents a phenyl group, and R3 and R4 each represents a C1-8 alkyl group; a group in which R2 represents a 3,4-methylenedioxyphenyl group, and R3 and R4 each represents a C1-8 alkyl group; and a group in which R2 represents a C1-8 alkyl group, and R3 and R4 are taken together to represent a C2-6 alkylene group;
more preferably a group in which R2, R3, and R4 each represents a C1-4 alkyl group; a group in which R2 represents a phenyl group, and R3 and R4 each represents a C1-4 alkyl group; a group in which R2 represents a 3,4-methylenedioxyphenyl group, and R3 and R4 each represents a C1-4 alkyl group;
and a group in which R2 represents a C1-4 alkyl group, and R3 and R4 are taken together to represent a C2-5 alkylene group, and
most preferably, the group 
xe2x80x83represents an xcex1,xcex1-dimethyl-3,4-methylenedioxybenzyl group, a t-butyl group, an xcex1,xcex1-dimethylbenzyl group or a 1-methylcyclopropyl group.
In the invention, as is apparent to one skilled in the art, the mark 
shows that the bond is in front of paper (at the xcex2-position) unless otherwise indicated; the mark 
indicates that the bond is on the other side of paper (at the xcex1-position) unless otherwise indicated; the mark 
shows that the compound has the bond at the xcex2-position or the xcex1-position or the compound is a mixture of these compounds; and the mark 
indicates that the compound is a mixture of a compound having the bond at the xcex2-position and a compound having the bond at the xcex1-position.
In the invention, all conceivable isomers are included in the scope thereof unless otherwise indicated. For example, an alkyl group, an alkoxy group and an alkylene group include straight-chain groups and branched groups. Isomers caused by the presence of an asymmetric carbon (e.g., R or S-forms, xcex1- or xcex2-forms, enantiomers, and diastereomers) and optically active compounds having optical rotation (i.e., D-, L-, d- or I-forms) are all included within the scope of the invention.
The compound represented by formula (I) can be produced by processes (1) and (2) described below, the processes according to Examples described below, or known processes.
(1) Among the compounds represented by formula (I), a compound in which R1 represents an amino-protective group, i.e., a compound represented by formula (I-2): 
xe2x80x83(wherein all symbols have the same meanings as described above) is prepared by reacting a compound represented by formula (V): 
xe2x80x83(wherein R5 has the same meaning as described above) and a compound represented by formula (VI): 
xe2x80x83(wherein all symbols have the same meanings as described above).
The reaction between the compound represented by formula (V) and the compound represented by formula (VI) is carried out in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran, toluene, dimethylformamide, or the like) in the presence of a base (e.g., lithium diisopropylamide (LDA), or the like) and a tertiary amine (e.g., tetramethylethylenediamine, or the like) at xe2x88x9278 to 0xc2x0 C.
(2) Among the compounds represented by formula (I), a compound in which R1 is a hydrogen atom, i.e., a compound represented by formula (I-1): 
xe2x80x83(wherein all symbols have the same meanings as described above) is prepared by subjecting the compound represented by formula (I-2) to a deprotection reaction of the amino-protecting group.
The deprotection reaction for the amino-protecting group includes, for example,
1) a deprotection reaction under alkaline conditions,
2) a deprotection reaction under acidic conditions, and
3) a deprotection reaction by hydrolysis.
More specifically,
1) the deprotection reaction under alkaline conditions is carried out, for example, at 0xc2x0 C. to 40xc2x0 C. in an organic solvent (e.g., methanol, tetrahydrofuran, dioxane, dimethylformamide, or the like) using an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, or the like), an alkaline earth metal hydroxide (e.g., barium hydroxide, calcium hydroxide, or the like), an organic amine (e.g., triethylamine, N-methylmorpholine, diisopropylethylamine, piperidine, or the like) or a quaternary ammonium salt (e.g., tetrabutylammonium fluoride, or the like) an aqueous solution thereof or a mixture thereof.
2) The deprotection reaction under acidic conditions is carried out, for example, at 0xc2x0 C. to 100xc2x0 C. in an organic solvent (e.g., methylene chloride, chloroform, dioxane, ethyl acetate, anisole, or the like) or without a solvent using an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, trimethylsilyl iodide, or the like) or an inorganic acid (e.g., hydrochloric acid, sulfuric acid, or the like), or a mixture thereof (e.g., hydrogen bromide/acetic acid, or the like).
3) The deprotection reaction by hydrolysis is carried out, for example, in an inert solvent (e.g., ethers (tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohols (methanol, ethanol, etc.), benzene solvents (benzene, toluene, etc.), ketones (acetone, methyl ethyl ketone, etc.), nitriles (acetonitrile, etc.), amides (dimethylformamide, etc.), water, ethyl acetate, acetic acid, or mixed solvent of two or more thereof) in the presence of a hydrogenation catalyst (e.g., palladium-carbon, palladium black, palladium, palladium hydroxide, platinum dioxide, nickel, Raney nickel, ruthenium chloride, or the like) and in the presence or absence of an inorganic acid (e.g., hydrochloric acid, sulfuric acid, hypochloric acid, boric acid, tetrafluoroboric acid, or the like) or an organic acid (e.g., acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic acid, or the like) in a hydrogen atmosphere either under normal pressure or under pressure or in the presence of ammonium formate at a 0xc2x0 C. to 200xc2x0 C. In using an acid, the acid may be used in the form of its salt.
As is easily understood by one skilled in the art, the desired compound of the invention can be easily obtained by a proper choice of these reactions.
The deprotection reaction of the compound represented by formula (I-2) is preferably carried out by the reaction under acidic conditions or the reaction by hydrolysis. The reaction under acidic conditions is more preferred.
The compound represented by formula (I-1) is allowed to react with the compound represented by formula (IV): 
(wherein R6 has the same meaning as described above) to produce the compound represented by formula (III): 
(wherein all symbols have the same meanings as described above). The reaction for producing the compound represented by formula (III) is an amidation.
The amidation is known in the art. It includes, for example,
1) a process using an acid halide,
2) a process using a mixed acid anhydride, and
3) a process using a condensing agent.
More specifically,
1) the process using an acid halide is carried out by, for example, reacting the compound represented by formula (IV) with an acid halide (e.g., oxalyl chloride thionyl chloride, or the like) in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran, or the like) or without a solvent at xe2x88x9220xc2x0 C. to a refluxing temperature and reacting the resulting acid halide with the compound represented by formula (I-1) in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran, or the like) in the presence of a tertiary amine (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, or the like) at xe2x88x9220xc2x0 C. to 40xc2x0 C.
2) The process using a mixed acid anhydride is carried out by, for example, reacting the compound represented by formula (IV) with an acid halide (e.g., pivaloyl chloride, tosyl chloride, mesyl chloride, or the like) or an acid derivative (e.g., ethyl chloroformate (ethyl chlorocarbonate), isobutyl chloroformate (isobutyl chlorocarbonate), or the like) in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran, or the like) or without a solvent in the presence of a tertiary amine (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, N-methylmorpholine, or the like) at xe2x88x9220xc2x0 C. to 40xc2x0 C. and reacting the resulting mixed acid anhydride with the compound represented by formula (I-1) in an inert organic solvent (e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuran, or the like) at xe2x88x9220xc2x0 C. to 40xc2x0 C.
3) The process using a condensing agent is conducted by, for example, reacting the compound represented by formula (IV) with the compound represented by formula (I-1) in an organic solvent (e.g., chloroform, methylene chloride, dimethylformamide, diethyl ether, tetrahydrofuran, or the like) or without a solvent in the presence or absence of a tertiary amine (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, or the like) using a condensing agent (e.g., 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1xe2x80x2-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodide, or the like) and with or without 1-hydroxybenztriazole (HOBt) at 0xc2x0 C. to 40xc2x0 C.
The reactions 1), 2) and 3) are preferably carried out in an atmosphere of an inert gas (e.g., argon, nitrogen, or the like) under anhydrous conditions.
The amidation between the compound represented by formula (I-1) and the compound represented by formula (IV) is preferably carried out by the process using a mixed acid anhydride.
The reaction for converting the compound represented by formula (III) into the compound represented by formula (II) can be carried out by the above deprotection reaction of the amino-protecting group.
The deprotection reaction of the amino-protecting group for converting the compound represented by formula (III) into the compound represented by formula (II) is preferably carried out by hydrolysis.
The compound represented by formula (V) and the compound represented by formula (VI) are produced by the process described in WO9824806 or Examples described below.
The compound represented by formula (IV) is produced by the process described in EP 528633 (JP-A-5-286946).
The other starting materials and reagents used in the present invention are known per se or can be prepared by known processes.
As is easily understood by one skilled in the art, the compounds represented by formulas (I-2), (I-1), (III) and (II) in their optically active form can be easily produced using an optically active compound as the compound represented by formula (V).
For example, among the compounds represented by formula (V), t-butyl N-((1R)-1-(Nxe2x80x2-methyl-Nxe2x80x2-methoxyaminocarbonyl)-2-methylpropyl)carbamate (CAS Registry No. 190260-92-5), t-butyl N-((1S)-1-(Nxe2x80x2-methyl-Nxe2x80x2-methoxyaminocarbonyl)-2-methylpropyl)carbamate (CAS Registry No. 160711-20-6), benzyl N-((1S)-1-(Nxe2x80x2-methyl-Nxe2x80x2-methoxyaminocarbonyl)-2-methylpropyl)carbamate (CAS Registry No. 114744-84-2), and the like are known. Use of these optically active compounds easily provides, for example, N-((1R)-1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)-2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetamide, N-((1S)-1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)-2-(5-benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetamide, and the like among the compounds represented by formula (III); and N-(1R)-1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)-2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetamide, N-((1S)-1-(2-t-butyl-1,3,4-oxadiazol-5-ylcarbonyl)-2-methylpropyl)-2-(5-amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)acetamide, and the like among the compounds represented by formula (II).
The product of each reaction in the invention is purified through common purification means, for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, column chromatography, washing, recrystallization, and the like. The purification may be carried out at each reaction or after completion of several reactions.
The compound represented by general formula (I) can be converted into a salt by a known method. The salt is preferably non-toxic and water-soluble. Examples of suitable salts include salts with alkali metals (e.g., potassium, sodium, and the like), salts with alkaline earth metals (e.g., calcium, magnesium, and the like), ammonium salts, and pharmaceutically acceptable salts with organic amines (e.g., tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine, N-methyl-D-glucamine, and the like).
The compound represented by formula (I) according to the present invention can be converted into an acid addition salt by a known process. The acid addition salt is preferably non-toxic and water-soluble. Examples of suitable acid addition salts include inorganic acid salts, such as hydrochlorides, hydrobromides, sulfates, phosphates, nitrates, and the like; and organic acid salts, such as acetates, trifluoroacetates, lactates, tartrates, oxalates, fumarates, maleates, citrates, benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates, isethionates, glucuronates, gluconates, and the like.
The compound represented by formula (I) according to the invention or a non-toxic salt thereof can be converted into a hydrate thereof by a known method.
Industrial Applicability
The process of the invention provides the compound represented by formula (II) through a fewer steps using the novel intermediate represented by formula (I) and is therefore useful as an efficient industrial process of production.